{"id":6312,"date":"2023-02-17T07:13:06","date_gmt":"2023-02-17T07:13:06","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2019-functional-consequences-of-a-kcnt1-variant-associated-with-status-dystonicus-and-early%e2%80%90onset-infantile-encephalopathy\/"},"modified":"2023-02-17T07:13:07","modified_gmt":"2023-02-17T07:13:07","slug":"2019-functional-consequences-of-a-kcnt1-variant-associated-with-status-dystonicus-and-early%e2%80%90onset-infantile-encephalopathy","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2019-functional-consequences-of-a-kcnt1-variant-associated-with-status-dystonicus-and-early%e2%80%90onset-infantile-encephalopathy\/","title":{"rendered":"2019 &#8211; Functional consequences of a KCNT1 variant associated with status dystonicus and early\u2010onset infantile encephalopathy"},"content":{"rendered":"<p>Objective: We identified a novel de novo KCNT1 variant in a patient with early\u2010infantile epileptic encephalopathy (EIEE) and status dystonicus, a life\u2010threatening movement disorder. We determined the functional consequences of this variant on the encoded KNa1.1 channel to investigate the molecular mechanisms responsible for this disorder. Methods: A retrospective case review of the proband is presented. We performed manual and automated electrophysiologic analyses of the KCNT1\u2010L437F variant expressed heterologously in Chinese hamster ovary (CHO) cells in the presence of channel activators\/blockers. Results: The KCNT1\u2010L437F variant, identified in a patient with refractory EIEE and status dystonicus, confers a gain\u2010of\u2010function channel phenotype characterized by instantaneous, voltage\u2010dependent activation. Channel openers do not further increase L437F channel function, suggesting maximal activation, whereas channel blockers similarly block wild\u2010type and variant channels. We further demonstrated that KCNT1 current can be measured on a high\u2010throughput automated electrophysiology platform with potential value for future screening of novel and repurposed pharmacotherapies. Interpretation: A novel pathogenic variant in KCNT1 associated with early\u2010onset, medication\u2010refractory epilepsy and dystonia causes gain\u2010of\u2010function with rapid activation kinetics. Our findings extend the genotype\u2013phenotype relationships of KCNT1 variants to include severe dystonia.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50],"therapeutic_areas":[55],"target_categories":[61,335],"target_families":[354],"targets":[286],"resource_keyword":[],"class_list":["post-6312","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","therapeutic_areas-cns","target_categories-voltage-gated-ion-channels","target_categories-intracellular-regulated-ion-channels","target_families-calcium-and-sodium-activated-potassium-channels-kca-and-kna","targets-kca4-1"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/6312","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=6312"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=6312"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=6312"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=6312"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=6312"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=6312"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=6312"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=6312"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=6312"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}